JP2022502406A - Method for preparing modified release type composite unit oral dosage form of doxylamine succinate and pyridoxine hydrochloride - Google Patents

Abstract

The present invention is a process for preparing a modified release composite unit oral dosage form comprising a plurality of modified release pellets of doxylamine or a salt thereof and a modified release pellet of pyridoxine or a salt thereof. It comprises coating a pellet of doxylamine with an active coating layer and an intermediate enteric coating layer and a pellet of pyridoxine with an inner active coating layer, wherein the coating step comprises an enteric coating and a modified release coating. It relates to a process comprising simultaneous spraying of a mixture containing an agent, as well as adding a pore-forming agent in powder form.

Description

The present invention prepares a modified release composite unit oral dosage form of modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof and pyridoxine or a modified release pellet of a pharmaceutically acceptable salt thereof. Regarding the method for.

Doxylamine is the international general name for (RS) -N, N-dimethyl-2- (1-phenyl-1-pyridin-2-yl-ethoxy) ethaneamine having a CAS number of 469-21-6. Doxylamine is a first-generation antihistamine that blocks H1 receptors competitively, reversibly and non-specifically, as well as other receptors (eg, central or peripheral muscarinic receptors). It is also a non-specific antagonist that can be blocked and has significant anticholinergic activity. Doxylamine is commonly used in the form of salts, specifically in the form of its succinate. The structure of doxylamine corresponds to formula (I) below:

Meanwhile, pyridoxine, which is also known as vitamin _{B 6} is an international common name of 4,5-bis (hydroxymethyl) -2-methylpyridine-3-ol having the CAS number 65-23-6 .. Pyridoxine is a water-soluble vitamin factor whose active form is pyridoxal phosphate ester. Pyridoxine acts as an enzymatic cofactor in many biochemical reactions involved in the digestive degradation of proteins and amino acids, as well as to a lesser extent lipids and carbohydrates. Pyridoxine is also involved in the metabolism of unsaturated fatty acids and is also a coenzyme for transaminase and decarboxylase that allows the conversion of tryptophan to nicotinic acid. Pyridoxine is generally used in the form of salts, specifically in the form of its hydrochlorides. The structure of pyridoxine corresponds to formula (II) below:

Doxylamine is commonly used alone as a short-term sedative and is also used in combination with other drugs to provide nocturnal relief for allergies and colds. Doxylamine is also used as an analgesic / sedative formulation in combination with the analgesics paracetamol (acetaminophen) and codeine, and is prescribed in pregnant women in combination with pyridoxine to prevent early morning vomiting. There is.

Modified and released oral dosage forms of doxylamine succinate and pyridoxine hydrochloride with different pharmacokinetic and pharmacological properties are disclosed in the latest technology.

Several double-release oral dosage forms of doxylamine succinate and pyridoxine hydrochloride and their preparation methods are disclosed in the latest technology. These double release oral dosage forms are formed by at least one immediate release composition and at least one modified release composition, provided that each one of the compositions is one or more of the active ingredients. have. This dosing system makes it possible to have an immediate release of one active ingredient and a modified release of the other active ingredient separately (see Patent Documents 1 and 2).

On the other hand, a hard capsule filled with a modified release pellet of doxylamine succinate and a modified release pellet of pyridoxine hydrochloride is sold under the name of Cariban. Cariban is used for symptomatic treatment of nausea and vomiting. In particular, the effects of doxylamine and pyridoxine begin to be observed 5 hours after ingestion, which is advantageous to allow long-term therapeutic effects and reduced drug intake. However, the preparation method is not disclosed in the latest technology.

The method used to prepare a composite unit oral dosage form (eg, a tablet or capsule with different pellets) determines the pharmacokinetic parameters of the active ingredient and the therapeutic activity of the composite unit dosage form. Is also determined. In particular, the therapeutic effect of the composite unit dosage form depends on the dissolution profile of the active ingredient from each one of the pellets and also on the uniformity between the pellets.

Therefore, as is known in the art, a uniform batch of composite unit oral dosages containing modified release pellets of both active ingredients, doxylamine and pyridoxine, indicating a suitable lysing profile for use in treatment. It is inferred that there is still a need to provide an inexpensive, robust, reproducible and scaled-up method for preparing things.

International Publication WO2013 / 123569 Gazette International Publication WO2016 / 029290 Gazette

We spray a mixture of modified release coating compositions onto (coated) inert nuclei, while simultaneously in solid form the active ingredient and / or pore-forming agent (and one if necessary). Suitable for use in treatment with long-term therapeutic effect by the preparation method of the present invention comprising coating by adding (or a plurality of pharmaceutically acceptable excipients or carriers) at an appropriate spray flow rate. A uniform batch of composite unit oral dosage forms with modified release pellets of both active ingredients of doxylamine or a pharmaceutically acceptable salt thereof and pyridoxine or a pharmaceutically acceptable salt thereof having a lytic profile. We have found that it is possible to obtain.

Specifically, we present a solution of the complex unit oral dosage form thus obtained by the method for preparing a modified release coating of both plurality of pellets of the present invention, which is the lysing profile of interest. That is, it has been found that it is possible to show the following dissolution profile:
10% to 35% by weight of doxylamine content dissolves in 0.1 N HCl medium (pH = 1) at 1 hour;
The medium is then replaced with a pH = 4.5 medium (0.05 M acetate buffer) and at 4 hours the cumulative 45% to 70% by weight of the initial doxylamine content dissolves;
The medium is then replaced with a medium with pH = 6.8 (0.05 M phosphate buffer) and at 7 hours, at least a cumulative 80% of the initial doxylamine content is dissolved;
10% to 35% by weight of the pyridoxine content dissolves in 0.1 N HCl medium (pH = 1) at 1 hour;
The medium is then replaced with a pH = 4.5 medium (0.05 M acetate buffer) and at 4 hours the cumulative 40% to 65% by weight of the initial pyridoxine content dissolves;
The medium is then replaced with a medium with pH = 6.8 (0.05 M phosphate buffer) and at 7 hours, at least a cumulative 80% of the initial pyridoxine content is dissolved;

However, the dissolution profile is measured at 37 ° C. ± 0.5 ° C. and 100 rpm using a United States Pharmacopeia Type II device (basket) with the composition in 900 mL of the corresponding medium / buffer.

Therefore, the method for preparing a modified release coating of both plurality of pellets of the present invention is such that the combined unit oral dosage form thus obtained is a modified duration of both active ingredients for at least 8 hours after administration. It is possible to bring about a release. The modified sustained release composition of the present invention is advantageous because it has the dual effect of immediate release and long-term release over a day, specifically over a full day after waking up.

Without being bound by any theory, the methods of the invention make it possible to obtain homogeneous types of pellets without the formation of agglomerates and powdered mixtures. It seems to be convenient to achieve the desired dissolution profile.

Moreover, the method of the invention also makes it possible to obtain both plurality of pellets with high uniformity of active ingredient content (ie, high interpellet uniformity). This means that each pellet has approximately the same amount of active ingredient, and therefore the composite unit oral dosage form filled with those pellets will always have a therapeutically effective amount of doxylamine or a pharmaceutical thereof. The method of the invention is convenient because it ensures that it has a pharmaceutically acceptable salt and pyridoxine or a pharmaceutically acceptable salt thereof. This means that underdose and overdose of the active ingredient in composite unit oral dosages can be avoided by using the methods of the invention.

Finally, we also present that the methods of the invention are cheaper, more robust, more reproducible, and easier to scale up than state-of-the-art methods. The method has also found to be convenient.

Thus, aspects of the invention are a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof and a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof. Including and
A first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof.
・ Inactive nucleus;
• A therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more dressings, one or more pore-forming agents, and one or more pharmaceuticals if necessary. An inner active coating layer containing an acceptable excipient;
An intermediate enteric release dressing containing one or more enteric coatings and one or more pore-forming agents; and-one or more enteric coatings and one or more Includes an outer modified release coating layer containing a modified release coating and one or more pore-forming agents.
And a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof.
・ Inactive nucleus;
An inner active dressing containing a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof; and one or more enteric coatings and one. A method for preparing a modified release complex unit oral dosage form comprising an outer modified release coating layer comprising one or more modified release dressings and one or more pore-forming agents.
The following process:
Doxylamine with an inner active coating layer and an intermediate enteric coating layer or pellets of pharmaceutically acceptable salts thereof, 2.0-7.5 wt% enteric coating and 15.0-35. Doxylamine or pharmaceutically thereof by co-spraying a mixture containing a weight ratio of 5.0% by weight of the modified release coating in a weight ratio of 5:95 to 30:70 and coating by adding the pore-forming agent in powder form. In the step of preparing the first plurality of modified release pellets of acceptable salt, the spray flow rate of the mixture containing the coating is 300-1200 mg / min per 1 kg of inert nuclei, and the pore-forming agent. The solid addition rate is 75-500 mg / min per 1 kg of inert nuclei, and the relationship between the spray flow rate of the mixture containing the coating and the addition rate of the pore-forming agent in solid form is 90: 10-10. 60:40, process,
And • Pyridoxin or pharmaceutically acceptable salt pellets thereof with an inner active coating layer, 2.0 to 7.5% by weight enteric coating and 15.0 to 35.0% by weight modification. By co-spraying a mixture containing a release coating in a weight ratio of 5:95 to 30:70 and coating by adding the pore-forming agent in powder form, the pyridoxin or a pharmaceutically acceptable salt thereof is the first. In the step of preparing a plurality of modified release pellets of 2, the spray flow rate of the mixture containing the coating agent is 300 to 1200 mg / min per 1 kg of inert nuclei, and the solid addition rate of the pore-forming agent is 1 kg. 75-500 mg / min per inert nucleus and the relationship between the spray flow rate of the mixture containing the coating and the rate of addition of the pore-forming agent is 90: 10-60: 40, a method comprising a step. Regarding.

All terms as used herein in this application are to be understood in their usual sense as is known in the art, unless otherwise specified. Other more specific definitions for certain terms, such as those used in this application, are as set forth below, and unless otherwise expressly defined are broader definitions. It is intended to be applied uniformly throughout the writing and claims.

For the purposes of the present invention, any range shown includes the endpoints of both the lower and upper bounds of the range. The ranges and values shown, such as temperature and time, shall be considered approximations, unless otherwise specified.

In addition, the terms "relation" and the term "relationship" have the same meaning and are used interchangeably. The term is used in the present invention because the relationship between the spray flow rate of the mixture containing the dressing and the rate of addition of the pore-forming agent in solid form is 90: 10-60: 40.

The method of the invention is a modified release composite unit oral containing multiple modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof and a modified release pellet of pyridoxine or a pharmaceutically acceptable salt thereof. A method for preparing a dosage form. The term "composite unit dosage form" defines a dosage form consisting of two or more units containing effective amounts of doxylamine and pyridoxine. Complex unit dosage forms are usually based on sub-units such as granules, pellets or mini-tablets. Composite unit dosage forms are usually delivered in hard gelatin capsules or converted to tablets. In one embodiment, the composite unit dosage form is a rigid capsule filled with pellets as sub-units with the active ingredient.

As disclosed above, the method of the invention prepares a composite unit dosage form comprising a plurality of two types of pellets. The term "pellet" refers to small particles with a nearly uniform shape and size produced by the extrusion method or by layer coating on the inert nucleus. "Small particles" refer to particles having a diameter, length, height or width of 100 μm to 3000 μm, specifically 300 μm to 2000 μm, and more specifically 600 μm to 1400 μm. A small particle is one in which the diameter, length, height or width of the smallest particle is at least about 1/2 of the average diameter, average length, average height or width of the particle, and the largest particle. If the diameter, length, height or width of the particles is at most about twice the average diameter, average length, average height or width of the particles, then they have a nearly uniform size. In that case, the terms "pellet", term "spherical pellet", term "bead", term "beadlet", term "spherical particle", term "spheroid" and term "microsphere" have the same meaning and are interchangeable. Used for. The term "granule" refers to small particles that do not have a nearly uniform shape and size as obtained by the granulation method. Generally, granules are not as uniform in size or shape as pellets. Therefore, the granules are less uniform due to their irregular surface, resulting in unacceptable dose uniformity and inadequate dissolution profile. Therefore, for the purposes of the present invention, the term "pellet" and the term "granule" are not the same and these terms are not interchangeable.

Similarly, the terms "modified release type dosage form" and the term "modified delivery type dosage form", as well as "modified release type" pellets and "modified delivery type" pellets have the same meaning and are interchangeable. Both terms should be understood as dosage forms or pellets that indicate the release of the active agent slower than the release of conventional immediate release pharmaceutical compositions administered by the same route. Generally, the term "modified release" indicates that the active ingredient is released from the pharmaceutical dosage form by controlled release, sustained release, long-term release or extended release.

In the context of the present invention, the terms "coating" and "thin film forming agent coating" have the same meaning and are used interchangeably. Both terms must be understood as an agent capable of forming a thin polymer-based coat on solid dosage forms (eg, tablets and pellets). Various examples of each of the various types of dressings are disclosed below.

In particular, the term "modified release dressing" is an agent capable of forming a thin film that allows the drug to be delivered at a given rate and / or location depending on the body's needs and disease state over a period of time. Is shown. Exemplary, but not limited to, "modified release polymers" and "modified delivery polymers" include polymers that provide controlled release, sustained release, long-term release or extended release. Examples of modified release coatings include, but are not limited to, acrylic polymers, various celluloses and derivatives thereof, shellac, zein, hydrogenated vegetable oils, hydrogenated castor oil, and mixtures thereof. Examples of suitable acrylic polymers include acrylic acid / methacrylic acid copolymers, methyl methacrylate copolymers, various ethoxyethyl methacrylates, cyanoethyl methacrylates, aminoalkyl methacrylate copolymers, poly (acrylic acid), poly (methacrylic acid), and methacrylics. Acid Alkylamide Copolymer, Poly (Methyl Methacrylic Acid), Poly (Acrylic Methacrylic Acid Anhydrous), Methyl Methacrylate, Polymethacrylate, Poly (Methyl Methacrylate) Polymer, Polyacrylamide, Aminoalkyl Methacrylic Acid Copolymer, Glycidyl Methacrylate Copolymer, Includes, but is not limited to, shelac, and mixtures thereof. The modified release polymer is selected from the group consisting of acrylic acid / methacrylic acid copolymers and shellac. Preferably, the modified release polymer is shellac. Modified release polymers include plasticizers (eg, triethyl citrate (TEC), polyethylene glycol (PEG), cetyl alcohol and stearyl alcohol, etc.), surfactants (eg, sodium lauryl sulfate, polysorbate and poloxamer, etc.), pigments. It can be accompanied by (eg, titanium dioxide, iron sesquioxide, etc.), lubricants (eg, talc, magnesium stearate or glyceryl monostearate, etc.), and mixtures thereof.

The term "binder" is incorporated into the formulation to facilitate the agglomeration of the powder into granules or pellets while mixing with a granulation solution (eg, water, aqueous alcohol mixture or other solvent). Indicates a substance. Examples of binders or binders include, but are not limited to, microcrystalline cellulose, hydroxypropylmethyl cellulose (HPMC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) 6000, guar gum, starch or shellac.

The term "intestinal release" refers to a composition or layer of a dosage form formulated to release the active ingredient when exposed to a characteristic aspect of the gastrointestinal tract. In one embodiment, the enteric material is pH sensitive and is affected by changes in pH encountered in the gastrointestinal tract (pH sensitive release). The enteric material typically remains insoluble at the pH of the stomach, followed by the release of the active ingredient in the higher pH environment of the downstream gastrointestinal tract (eg, often the duodenum, or sometimes the colon). enable. In another embodiment, the enteric material comprises an enzymatically degradable polymer that is degraded by a bacterial enzyme present in the lower gastrointestinal tract, specifically by a bacterial enzyme present in the colon. If required, the unit dosage form is formulated with a pH sensitive enteric material designed to result in release within a suitable few hours when at a specific pH or above a specific pH. .. In various embodiments, the particular pH can be, for example, about 4 to about 7, eg, about 4.5, 5, 5.5, 6, 6.5, 6.8 or 7. And so on. In the context of the present invention, the term "intestinal release coating" forms a thin film that allows doxylamine and pyridoxine to be delivered when exposed to the characteristic aspects of the gastrointestinal tract as defined above. Indicates a drug that can. Various materials used, for example, as coatings for enteric release formulations are widely known in the art, including, but not limited to, cellulose-based: Polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate, hydroxypropylmethyl phthalate, methyl cellulose, ethyl cellulose, cellulose acetate, phthalate acetate, trimellitoacetate cellulose and carboxymethyl cellulose. Sodium and the like; polymers and copolymers formed from acrylate polymers and copolymers of acrylate, preferably acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate, and trade names below. Other Methacrylic Acids Commercially Available in: Acryl-EZE® (Colorcon, USA), Eudragit® (Rohm Polymer; Westerstat, Germany), which includes Eudragit® L30D-55 and L100-55 (soluble at pH 5.5 or higher), Polymer® L100 and L12.5 (soluble at pH 6.0 or higher), Polymer® S, S12.5 and FS 30D (from). Includes (soluble above pH 7.0) as a result of high degree of esterification), and Eudragits® NE, NM, RL and RS (water-insoluble polymers with different degrees of permeability and swelling); vinyl. Polymers and vinyl copolymers such as polyvinylpyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl acetate crotonic acid copolymer and ethylene-vinyl acetate copolymer; enzymatically degradable polymers such as azopolymers, pectin, chitosan, amylose and guar gum. ; Zein and Sherac. Combinations of different enteric materials may also be used. Multilayer coatings using different polymers may also be applied. The characteristics, manufacture and design of intestinal delivery systems are widely known to those of skill in the art. In certain embodiments, the enteric coating is a copolymer of methacrylic acid and methyl methacrylate, a copolymer of methacrylic acid and methyl acrylate, cellulose acetate phthalate, hydroxypropylmethyl phthalate, polyvinyl acetate phthalate, sodium alginate, It is selected from the group consisting of cellulose acetate trimeritate, as well as mixtures thereof. More specifically, there is Eudragit L® (registered trademark), for example, Eudragit L100 (sold by Evonik) and the like.

As defined above, the method of the invention comprises a first plurality of pellets comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of pyridoxine or a pharmaceutical thereof. Includes preparing a second plurality of pellets containing a salt that is acceptable to the patient.

The term "therapeutic effective amount", when used herein, is sufficient or addressed to prevent the development of one or more symptoms of the disease being treated when administered. The amount of active ingredient per compound unit dosage form that is sufficient to alleviate one or more of the symptoms of the disease to some extent is shown. The particular dose of compound administered in accordance with the present invention will be determined by the circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations. ..

As used herein, the term "pharmaceutically acceptable salt" includes any salt formed from a pharmaceutically acceptable non-toxic acid, including inorganic or organic acids. do. If the salt is used for therapeutic purposes, there are no restrictions on the salt, except that the salt must be pharmaceutically acceptable. Since doxylamine and pyridoxine are basic compounds, various salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, among other things, acetic acid, benzenesulfonic acid, benzoic acid, gypsum sulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, lactic acid, maleic acid, apple. Includes acids, mandelic acid, methanesulfonic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid or p-toluenesulfonic acid.

Preparation of pharmaceutically acceptable salts of doxylamine and pyridoxine can be performed by various methods known in the art. For example, pharmaceutically acceptable salts thereof can be prepared from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts are such, for example, in the free acid or free base form of these compounds in water or organic solvents or mixtures thereof, with suitable pharmaceutically acceptable bases or acids in stoichiometric amounts. Prepared by reacting.

In one embodiment, the method comprises a first plurality of pellets comprising a therapeutically effective amount of a pharmaceutically acceptable salt of doxylamine, specifically a therapeutically effective amount of succinate of doxylamine. Includes preparing. In one embodiment, the method is 5 mg to 50 mg doxylamine succinate per composite unit dosage form, specifically 6 mg to 40 mg, 7 mg to 30 mg, 8 mg to 20 mg, more specifically 9 mg to 11 mg succinic acid. It comprises preparing a composite unit dosage form having a first plurality of pellets containing doxylamine. In certain embodiments, the method comprises preparing a composite unit dosage form having a first plurality of pellets having 10 mg of doxylamine succinate per composite unit dosage form. In one embodiment, the method prepares a second plurality of pellets comprising a therapeutically effective amount of a pharmaceutically acceptable salt of pyridoxine, specifically a therapeutically effective amount of pyridoxine hydrochloride. Including that. In one embodiment, the method comprises 5 mg to 50 mg pyridoxine hydrochloride per composite unit dosage form, specifically 6 mg to 40 mg, 7 mg to 30 mg, 8 mg to 20 mg, more specifically 9 mg to 11 mg pyridoxine hydrochloride. Includes preparing a composite unit dosage form with a second plurality of pellets comprising. In certain embodiments, the method comprises preparing a composite unit dosage form having a first plurality of pellets having 10 mg of pyridoxine hydrochloride per composite unit dosage form. In one embodiment, the method comprises a first plurality of pellets comprising a therapeutically effective amount of a pharmaceutically acceptable salt of doxylamine, specifically a therapeutically effective amount of succinate of doxylamine. And prepare a composite unit dosage form comprising a second plurality of pellets comprising a therapeutically effective amount of a pharmaceutically acceptable salt of pyridoxine, specifically a therapeutically effective amount of pyridoxine hydrochloride. Including doing. In one embodiment, the method comprises a first plurality of pellets comprising 5 mg to 50 mg doxylamine succinate per composite unit dosage form, specifically 10 mg doxylamine succinate per composite unit dosage form. To prepare a composite unit dosage form comprising a second plurality of pellets comprising 5 mg to 50 mg pyridoxyl hydrochloride per composite unit dosage form, specifically 10 mg pyridoxyl hydrochloride per composite unit dosage form. include. In certain embodiments, the method comprises a first plurality of pellets containing 10 mg doxylamine succinate per composite unit dosage form and a second plurality of pellets containing 10 mg pyridoxine hydrochloride per composite unit dosage form. Includes preparation.

In one embodiment, the method comprises a therapeutically effective amount of a pharmaceutically acceptable salt of doxylamine, specifically a therapeutically effective amount of succinate of doxylamine in a first dose of 20 mg to 220 mg. 20 mg to 220 mg, including multiple pellets of pyridoxine and a therapeutically effective amount of a pharmaceutically acceptable salt of pyridoxine, specifically a therapeutically effective amount of a pharmaceutically acceptable salt of pyridoxine hydrochloride. Includes preparing a composite unit dosage form comprising a second plurality of pellets. In one embodiment, the method comprises a first plurality of pellets of 20 mg to 220 mg, specifically 60 mg, comprising 5 mg to 50 mg of doxylamine succinate, specifically 10 mg of doxylamine succinate, and 5 mg. It comprises preparing a composite unit dosage form comprising ~ 50 mg of pyridoxine hydrochloride, specifically 20-220 mg containing 10 mg of pyridoxine hydrochloride, specifically 60 mg of a second plurality of pellets. In one embodiment, the method comprises a first plurality of pellets comprising 5 mg to 50 mg of doxylamine succinate, specifically 10 mg of doxylamine succinate, and 5 mg to 50 mg of pyridoxine hydrochloride, specifically. Includes preparing a composite unit dosage form comprising a second plurality of pellets comprising 10 mg pyridoxine hydrochloride. In certain embodiments, the method comprises preparing a first plurality of pellets containing 10 mg of doxylamine succinate and a second plurality of pellets containing 10 mg of pyridoxine hydrochloride.

In one embodiment, the method is a therapeutic effect of a pharmaceutically acceptable salt of doxylamine having a particle size of 1 μm to 250 μm, specifically 1 μm to 150 μm, more specifically less than 100 μm. Contains the preparation of a composite unit dosage form comprising a first plurality of pellets comprising an amount of the above-mentioned amount. In one embodiment, the method is more specific, wherein doxylamine or a salt thereof, in particular doxylamine succinate, has a D90 particle diameter of 1 μm to 250 μm, specifically a D90 particle diameter of 1 μm to 150 μm. Is a method having a D90 particle diameter of less than 100 μm.

Selection of particle size range or size fraction by sieving is widely known. One standard way to define a particle size distribution in a sample of particles is to refer to the values of D10, D50 and D90. D10 is the particle diameter value at which 10% of the particle population is below it. D50 is a particle diameter value in which 50% of the population is below it and 50% of the population is above it. D50 is also known as the median particle size value. D90 is the particle diameter value at which 90% of the population is below it.

In one embodiment, the method prepares a composite unit dosage form comprising a first plurality of pellets comprising a therapeutically effective amount of a pharmaceutically acceptable salt of pyridoxine having a particle size of 500 μm or less. Including that. In one embodiment, the method is such that pyridoxine or a salt thereof, in particular pyridoxine hydrochloride, has a particle size of 1 μm to 250 μm, specifically a particle size of 1 μm to 150 μm, more specifically 100 μm. A method having a particle size of less than.

The particle size of the active ingredient can be measured by any method disclosed in the state of the art. Examples of commonly used methods for measuring particle size are dynamic light scattering (DLS), which reports a number average diameter value, atomic force microscopy (AFM), or transmission for measuring dried particles. Examples include electron microscopy (TEM), laser diffraction (Laser Masterizer, Me theory; ISO1332-1), and methods by sedimentation analysis (Sedigraph-Stokes' law; ISO13317-3).

The term "pore-forming agent" refers to any agent capable of forming one or more pores in a shell / coating to allow modified release of the active ingredient. The pore-forming agent can be organic or inorganic or any combination thereof. Examples of pore-forming agents include talc, polyethylene glycol (PEG), propylene glycol, isopropyl alcohol, glycerol, lactose, glucose, sucrose, mannitol, sorbitol, sodium chloride, potassium chloride, hydroxypropyl cellulose, pulverized sugar, hydroxy. Includes, but is not limited to, propylmethyl cellulose (HPMC), polyvinyl alcohol, methacrylic acid copolymers, or mixtures thereof. In one embodiment, the pore-forming agent is selected from the group consisting of talc, pulverized sugar, sodium or potassium chloride, and mixtures thereof. In one embodiment, the method is a method in which the pore forming agent has a D90 particle diameter of 250 μm or less, specifically a D90 particle diameter of less than 150 μm, more specifically a D90 particle diameter of less than 100 μm. Is. In certain embodiments, the method is that the pore-forming agent is talc with a D90 particle diameter of less than 75 μm.

The particle size of the pore forming agent can be measured by any method disclosed in the latest technology. In particular, the methods used in the present invention for measuring particle size include a laser diffraction method (Laser Masterizer, Me theory; ISO1332-1) and a sedimentation analysis method (Sedigraph-Stokes' law; ISO13317-3). ).

The term "inert nucleus" refers to a neutral microsphere that can have one or more of the following substances in its composition: sorbitol, mannitol, saccharose, starch, microcrystalline cellulose, lactose, glucose, trehalose, Maltitol or fructose. The initial size of this inert nucleus can be between 200 and 1800 micrometers. In one embodiment, the Inactive Nuclei is a neutral microsphere of a mixture of sucrose and starch.

In one embodiment, the method comprises preparing a composite unit dosage form that may contain one or more pharmaceutically acceptable excipients or carriers. The term "pharmaceutically acceptable excipient or carrier" refers to such an excipient or carrier that is suitable for use in pharmaceutical technology for preparing compositions with medical uses. Suitable excipients and / or carriers, as well as their amounts, can be readily determined by one of ordinary skill in the art according to the type of formulation prepared. In one embodiment, the modified release composite unit dosage form of the invention further comprises a binder, an alkaline agent, a flow enhancer, a surfactant, or a mixture thereof.

As mentioned above, the methods of the invention are pellets of doxylamine or a pharmaceutically acceptable salt thereof having an active layer and an intermediate enteric coating layer, and pyridoxin having an inner active coating layer or the like thereof. It comprises coating separately from pharmaceutically acceptable salt pellets, in which case the modified release coating step is 2.0-7.5 wt% enteric coating and 15.0-35.0. A mixture containing a weight percent modified release coating in a weight ratio of 5:95 to 30:70 was simultaneously sprayed and the pore-forming agent was added in powder form, provided that the spray flow rate of the mixture containing the coating was high. 300-1200 mg / min per 1 kg of inert nuclei, the solid addition rate of the pore-forming agent is 75-500 mg / min per 1 kg of inactive nuclei, specifically per 1 kg of inactive nuclei. It is 85-425 mg / min, and the relationship between the spray flow rate of the mixture containing the coating and the rate of addition of the pore-forming agent in solid form is 90: 10-60: 40. This means that the method is carried out by spraying the mixture with the coating and at the same time adding the ingredients in powder form. In one embodiment, the method is a method in which a mixture comprising an enteric coating and a modified release coating as defined in the present invention has a weight ratio of 5:95 to 30:70. In one embodiment, the method comprises 5 mixing the mixture with a methacrylic acid-methyl methacrylate copolymer (1: 1) (Eudragit L) as an enteric coating and a (dewaxing) shellac as a modified release coating. A method as defined above, comprising: 95-30: 70 weight ratios, specifically 8:92-20: 80 weight ratios. In one embodiment, the method is such that the spray flow rate of the mixture containing the coating is 300-1200 mg / min per 1 Kg of Inactive Nuclei, specifically 385-1000 g / min per 1 Kg of Inactive Nuclei. There is a way.

In one embodiment, the method of the invention separately coats pellets of doxylamine or a pharmaceutically acceptable salt thereof having an active layer and an intermediate enteric coating layer as defined above. Including, in that case, the method is a method in which the solid addition rate of the pore-forming agent is 88-195 mg / min per 1 kg of inert nuclei. In one embodiment, the method has a relationship of 90: 10-60: 40 between the spray flow rate of the mixture containing the dressing and the solid addition rate of the pore-forming agent, specifically 90: 10-10. It is a method that is 70:30. In one embodiment, the method comprises a mixture comprising 2.5-7.5% enteric coating and 15-30% modified release coating, with one or more organic solvents particularly non-1 kg. An amount of 85-290 g of solvent per active nucleus, specifically 250-290 g of solvent per 1 kg of inert nucleus, more specifically 270-285 g of solvent per 1 kg of inert nucleus. The method is a solution that further comprises in the amount of.

In one embodiment, the method of the invention comprises separately coating a pellet of pyridoxine or a pharmaceutically acceptable salt thereof having an inner active coating layer, in which case the method comprises pore formation. The method is such that the solid addition rate of the agent is 193 to 425 mg / min per 1 kg of inert nucleus.

In one embodiment, the method has a relationship between the spray flow rate of the mixture containing the dressing and the solid addition rate of the pore-forming agent 90: 10-60: 40, specifically 80:20 to 60:40. It is a method of 60:40. In one embodiment, the method comprises a mixture comprising 2.5-5.5% enteric coating and 20-35% modified release coating, specifically 1 kg of one or more organic solvents. With an amount of 85-100 g of solvent per 1 Kg of Inactive Nucleus, specifically 90-95 g of solvent per 1 Kg of Inactive Nucleus, more specifically 280-290 g per 1 Kg of Inactive Nucleus. The method is a solution further comprising the amount of the solvent of.

In one embodiment, the method of the invention is a pellet of doxylamine or a pharmaceutically acceptable salt thereof having an active layer and an intermediate enteric coating layer as defined above, or an active coating on the inside. A mixture comprising a separately coated pellet of pyridoxyl or a pharmaceutically acceptable salt thereof having a layer and containing an enteric coating and a modified release coating is an _{alcohol (C 1 to} C ₄ ), (C _1). ~ C ₄ ) Alkyl-CO- (C ₁ ~ C ₄ ) Alkyl, (C ₁ ~ C ₄ ) Alkyl-CO-O- (C ₁ ~ C ₄ ) Alkyl, water and mixtures thereof. A method that is a solution further comprising one or more organic solvents. The term "alcohol" refers to an "alkane" in which at least one hydrogen atom is substituted with a hydroxyl group and contains the number of carbon atoms specified in the description or claim. The term "alkane" refers to a saturated branched or linear hydrocarbon containing the number of carbon atoms specified in the description or claim. Examples include methanol, ethanol, n-propanol, iso-propanol, butanol, iso-butanol and sec-butanol. The term "alkyl" refers to a saturated linear or branched hydrocarbon chain containing the number of carbon atoms specified in the description or claim. Examples include, among others, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl groups. In one embodiment, the method is selected from the group consisting of a mixture comprising an enteric coating and a modified release coating consisting of ethanol, 2-propanol, methanol, acetone, butanone, ethyl acetate, water and mixtures thereof. A method further comprising one or more organic solvents, specifically a solution further comprising one or more organic solvents selected from ethanol, acetone, water and mixtures thereof.

In one embodiment, the methods of the invention are pellets of doxylamine or a pharmaceutically acceptable salt thereof having an active layer and an intermediate enteric coating layer, and pyridoxine having an inner active coating layer or a pharmaceutical thereof. Includes separate coating with acceptable salt pellets, provided that the air flow is 0-20 m ³ / h per 1 kg of Inactive Nuclei, specifically per 1 Kg of Inactive Nuclei. It is 0 to ⁴ m 3 / h. Air flow is controlled using an anemometer-type air intake detection system installed in the duct between the fan and the coated pan, or using another equivalent system.

In one embodiment, the methods of the invention are pellets of doxylamine or a pharmaceutically acceptable salt thereof having an active layer and an intermediate enteric coating layer, and pyridoxine having an inner active coating layer or a pharmaceutical thereof. Includes coating separately with acceptable salt pellets, provided that the core temperature of the pellet during the coating process is 5 ° C to 50 ° C, specifically 10 ° C to 30 ° C. More specifically, it is 15 ° C to 25 ° C. The temperature is controlled using a calibrated PT100 sensor in direct contact with the pellet in the coating. However, temperature may be controlled using an equivalent system.

In one embodiment, the method of the invention is a pellet of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and an intermediate enteric coating layer, and a pyridoxine having an inner active coating layer. Or comprising separately coating with its pharmaceutically acceptable salt pellets, provided that the rotation speed is 0 to 50 rpm, specifically 2 to 25 rpm, more specifically 10 to 20 rpm. Is. The rotary pan speed can be controlled by any method known in the latest technology. In particular, the method used in the present invention is a method by using an integrated tachometer.

In one embodiment, where the method of the invention comprises coating pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and an intermediate enteric coating layer. The coating step comprises spraying a mixture containing 2.0 to 7.5% by weight of enteric coating and 15% to 35% by weight of modified release coating, provided that with the enteric coating. The weight ratio with the modified release coating is 15:85-25:75. Specifically, the mixture is 4-7% by weight of methacrylic acid-methyl methacrylate copolymer (1: 1) (Eudragit L) as an enteric coating and 15-25% by weight of a modified release coating. (Detachable) Shellac is included in a weight ratio of 15:85-25:75.

In one embodiment, if the method of the invention comprises coating a pellet of pyridoxin having an inner active coating layer or a pharmaceutically acceptable salt thereof, in which case the coating step is 2 Includes spraying a mixture containing 0-7.5% by weight enteric coating and 15-35% modified release coating, specifically 20-35% modified release coating. , The weight ratio between the enteric coating and the modified release coating is 5:95-30:70. Specifically, the mixture is 2.0-5% by weight of a methacrylic acid-methyl methacrylate copolymer (1: 1) (Eudragit L) as an enteric coating and 25-35% by weight of a modified release coating. % (Detachable) shelac is included in a weight ratio of 5:95 to 15:85.

In one embodiment, where the method of the invention comprises the step of coating a pellet of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and an intermediate enteric coating layer. The coating step simultaneously sprays a mixture containing 2.0-7.5% by weight of enteric coating and 15-35% by weight of modified release coating in a weight ratio of 5:95-30:70. It involves adding the pore-forming agent in powder form, provided that the spray flow rate of the mixture containing the coating is 300-1200 mg / min per 1 kg of inert nuclei, specifically per 1 Kg of inactive nuclei. More specifically, it is 445 to 1000 g / min, more specifically about 890 mg / min per 1 kg of pellets, and the solid addition rate of the pore-forming agent is 88-195 mg / min per 1 kg of inert nuclei. Specifically, it is 178 mg / min per 1 kg of pellets, and the relationship between the spray flow rate of the mixture containing the coating agent and the solid addition rate of the pore-forming agent is 90:10 to 70:30. It is 85: 15-75: 25, more specifically 83:17. This means that the method is carried out by spraying the mixture with the coating and at the same time adding the ingredients in powder form. In one embodiment, the method comprises a mixture comprising an enteric coating and a modified release coating as defined in the present invention having a weight ratio of 10:90 to 30:70, specifically 15:85. A method having a weight ratio of ~ 25: 75. In one embodiment, the method comprises a mixture of methacrylic acid-methyl methacrylate copolymer (1: 1) (Eudragit L) as an enteric coating and (dewaxing) shelac as a modified release coating. It is a method of including in a weight ratio of: 85 to 25:75, specifically in a weight ratio of 18:82 to 22:78, and more specifically in a weight ratio of 20:80. In one embodiment, the method is such that the spray flow rate of the mixture containing the coating is 300-1200 mg / min per 1 kg of inert nucleus, specifically at 445-1000 mg / min per 1 kg of inert nucleus. There is, more specifically, a method of 890 mg / min per 1 kg of pellets. In one embodiment, the method is a method in which the solid addition rate of the pore-forming agent is 88-195 mg / min per 1 kg of inert nucleus, more specifically 178 mg / min per 1 kg pellet. .. In one embodiment, the method has a relationship of 85: 15-75: 25 between the spray flow rate of the mixture containing the dressing and the solid addition rate of the pore-forming agent, specifically at 83:17. There is a way. In one embodiment, the method comprises 2 to 7.5% by weight of an enteric coating as defined above, specifically methacrylic acid-methyl methacrylate copolymer (Eudragit L) and 15-35 weight by weight. The mixture containing% of the modified release coating is a solvent amount of one or more organic solvents, specifically 275-290 g / min per 1 kg of pellets, more specifically 282 g per 1 kg of pellets. A solution further comprising an amount of solvent, wherein the mixture has a total solvent concentration of 72-78% by weight. In one embodiment, the method is a method in which the mixture comprising the enteric coating and the modified release coating is a solution further comprising one or more organic solvents as defined above.

In one embodiment, if the method of the invention comprises the step of coating a pellet of pyridoxin having an inner active coating layer or a pharmaceutically acceptable salt thereof, in which case the coating step is 2 .0 to 7.5% by weight enteric coating, specifically 2 to 5.5% by weight enteric coating and 15 to 35% by weight modified release coating 5: 95-25: Simultaneous spraying of the mixture containing at a weight ratio of 75 and addition of the pore-forming agent in powder form, provided that the spray flow rate of the mixture containing the coating is 385-850 mg / min per 1 kg of inert nuclei. The solid addition rate of the pore-forming agent is 193 to 425 mg / min per 1 kg of inert nuclei, and the relationship between the spray flow rate of the mixture containing the coating and the solid addition rate of the pore-forming agent is 80: It is 20 to 60:40. This means that the method is carried out by spraying the mixture with the coating and at the same time adding the ingredients in powder form. In one embodiment, the method is a method in which a mixture comprising an enteric coating and a modified release coating as defined in the present invention has a weight ratio of 5:95 to 30:70. In one embodiment, the method comprises 5 mixing the mixture with a methacrylic acid-methyl methacrylate copolymer (1: 1) (Eudragit L) as an enteric coating and a (dewaxing) shelac as a modified release coating. It is a method of including in a weight ratio of: 95 to 25:75, specifically in a weight ratio of 5:95 to 15:85, and more specifically in a weight ratio of 9:91. In one embodiment, the method is a method in which the spray flow rate of the mixture containing the coating is 385-850 mg / min per 1 kg of inert nucleus, specifically 773 mg / min per 1 kg of inert nucleus. Is. In one embodiment, the method is such that the solid addition rate of the pore-forming agent, specifically the solid addition rate of talc, is 193 to 425 mg / min per 1 kg of the Inactive Nuclei, specifically 1 kg. The method is 387 mg / min per inert nucleus. In one embodiment, the method has a relationship between the spray flow rate of the mixture containing the dressing and the solid addition rate of the pore-forming agent 90: 10-60: 40, specifically 75: 25-. It is a method of 65:35, more specifically 67:33. In one embodiment, the method is a mixture comprising 2.0-7.5% enteric coating and 15-35% modified release coating, specifically 1 kg of one or more organic solvents. A solution further comprising 90-95 g of solvent per pellet, more specifically 93 g of solvent per 1 kg of pellet, wherein the mixture has a total solvent concentration of 65-70 wt%, more specific. It is a method having 68% by weight of a solvent. In one embodiment, the method is a method in which the mixture comprising the enteric coating and the modified release coating is a solution further comprising one or more organic solvents as defined above.

In one embodiment, the methods of the invention further include simultaneous spraying of a mixture containing 30-40% by weight of one or more coatings, and a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof. , Specifically by adding a powdered mixture of doxylamine succinate, 22-30% by weight pore-forming agent and, if necessary, one or more pharmaceutically acceptable excipients. A pre-step of separately coating the inert nuclei, the spray flow rate of the mixture containing 30-40% by weight of one or more excipients is 445-1000 mg / min per 1 kg of inactive nuclei. The solid addition rate of the powdered mixture is 1.64 to 3.62 g / min per 1 kg of inert nucleus, and the relationship between the spray flow rate of the mixture containing the coating and the solid addition rate of the powdered mixture Including the pre-step, which is 15:85-25:75. In one embodiment, the method is a solution in which a mixture containing 30-40% by weight of one or more of the dressings further comprises one or more organic solvents, specifically in an amount of 60-70% by weight. Is the method. In one embodiment, the method is one or more organic in which the mixture containing the coating is selected from the group consisting of ethanol, 2-propanol, methanol, acetone, butanone, ethyl acetate and water, or mixtures thereof. It is a method that is a solution further containing a solvent.

In one embodiment, the methods of the invention further include simultaneous spraying of a mixture containing 30-40% by weight of one or more coatings, and a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof. By adding a powdered mixture of doxylamine succinate, specifically 22-30% by weight of a pore-forming agent and, if necessary, one or more pharmaceutically acceptable excipients. A pre-step of separately coating the inert nuclei, the spray flow rate of the mixture containing 30-40% by weight of one or more excipients is 445-1000 mg / min per 1 kg of inactive nuclei. The solid addition rate of the powdered mixture is 1.64 to 3.62 g / min per 1 kg of inert nucleus, and the relationship between the spray flow rate of the mixture containing the coating and the solid addition rate of the powdered mixture is 15: 85-25: 75 and the coating is selected from the group consisting of polyvinylpyrrolidone, shelac, hydroxypropylmethylcellulose, hydroxypropylcellulose and microcrystalline cellulose, and mixtures thereof, specifically polyvinylpyrrolidone and Including the pre-step, which is a mixture of shellac. Specifically, a mixture containing 30-40% by weight of one or more coatings is a mixture of polyvinylpyrrolidone K30 and (dewaxed) shellac in a weight ratio of 10:90-18:82 of the solid coating. (This value is equivalent to the weight ratio from 20:80 to 30:70 polyvinylpyrrolidone and shellac). More specifically, a solution of polyvinylpyrrolidone K-30 (20% ethanol solution) and a (dewaxing) shellac solution (40% w / w ethanol solution) at 20:80 to 40:60. Mixtures at a weight ratio, specifically a mixture at a weight ratio of 30:70.

In one embodiment, the methods of the invention further include simultaneous spraying of a mixture containing 30-40% by weight of one or more coatings, and a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof. , Specifically by adding a powdered mixture of doxylamine succinate, 22-30% by weight pore-forming agent and, if necessary, one or more pharmaceutically acceptable excipients. A pre-step of separately coating the inert nuclei, the spray flow rate of the mixture containing 30-40% by weight of one or more excipients is 445-1000 mg / min per 1 kg of inactive nuclei. The solid addition rate of the powdered mixture is 1.64 to 3.62 g / min per 1 kg of inert nucleus, and the relationship between the spray flow rate of the mixture containing the coating and the solid addition rate of the powdered mixture Including the pre-step, which is 15:85-30:70. In one embodiment, the method is such that the mixture containing 30-40% by weight of one or more of the coatings is 61-71 g per 1 kg of inert nucleus, specifically 1 kg of organic solvent. A solution further comprising a total amount of solvent, more specifically 66 g of solvent per 1 kg of Inactive Nucleus, wherein the mixture has a total solvent concentration of 0-70 wt%. In one embodiment, the method is a method in which the pore-forming agent is selected from talc, pulverized sugar, sodium chloride or potassium chloride, and mixtures thereof, specifically talc. In one embodiment, the method is a method in which the mixture containing the dressing is a solution further comprising one or more organic solvents as defined above. In one embodiment, the methods of the invention further include simultaneous spraying of a mixture containing 30-40% by weight of one or more excipients, and a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof. , Specifically doxylamine succinate, 22-30% by weight pore-forming agent and, if necessary, one or more pharmaceutically acceptable excipients as defined above. A pre-step of separately coating an inert nucleus by adding a powdered mixture, wherein the pharmaceutically acceptable excipient is one or more flow promoters, fillers, wicking. Includes pre-steps selected from the group consisting of agents or mixtures thereof.

The term "flow accelerator" refers to a substance that improves the flow properties of a powder mixture in the dry state. Materials commonly used as flow promoters include magnesium stearate, colloidal silicon dioxide or talc. In one embodiment, the composition of the invention comprises a pharmaceutically acceptable excipient or carrier comprising one or more flow promoters, preferably comprising colloidal silicon dioxide, more preferably Aerosil 200. It is a composition containing Pharma.

The term "filler" refers to a material added to increase the dosage form when the active ingredient is not present in sufficient quantity. Materials commonly used as fillers include lactose, sucrose, mannitol, dicalcium phosphate dehydrated products, starch, cellulose and microcrystalline cellulose. In one embodiment, the composition of the invention is a composition comprising one or more fillers of a pharmaceutically acceptable excipient or carrier, preferably comprising sucrose, starch or microcrystalline cellulose. ..

The term "wicking agent" refers to a material capable of drawing water into the porous network of delivery devices. The wicking agent can be physically adsorbed with water. The role of the wicking agent is to act like a carrier and facilitate the entry of water into the inner surface of the core. Materials commonly used as wicking agents include sodium lauryl sulfate, kaolin, titanium dioxide, alumina, bentonite, magnesium aluminum silicate, povidone and colloidal silicon dioxide (Aerosil). In one embodiment, the compositions of the invention comprise a wicking agent with one or more pharmaceutically acceptable excipients or carriers, preferably kaolin, titanium dioxide, alumina, bentonite, silicic acid. A composition comprising aluminum magnesium, povidone and colloidal silicon dioxide (Aerosil). In one embodiment, the compositions of the invention comprise a wicking agent with one or more pharmaceutically acceptable excipients or carriers, preferably povidone or colloidal silicon dioxide (Aerosil) or them. It is a composition containing a mixture of.

In one embodiment, the methods of the invention further include simultaneous spraying of a mixture containing 30-40% by weight of one or more coatings, and a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof. , Specifically a powdered mixture of doxylamine succinate, 22-30% by weight pore-forming agent and one or more pharmaceutically acceptable excipients as defined above. Thereby, in the pre-step of separately coating the inactive nuclei, 445-1000 mg / min per 1 Kg of inactive nuclei of a mixture containing 30-40% by weight of one or more excipients. The spray flow rate of the powdered mixture is 1.64 to 3.62 g / min per 1 kg of inert nucleus, and the relationship between the spray flow rate of the mixture containing the coating and the solid addition rate of the powdered mixture. Includes the pre-step, which is 15:85-30:70. In one embodiment, doxylamine or a pharmaceutically acceptable salt thereof, specifically doxylamine succinate, has a particle size of 100 μm or less.

In one embodiment, the methods of the invention further include simultaneous spraying of a mixture containing 30-45% of one or more coatings, and a therapeutically effective amount of pyridoxin or a pharmaceutically acceptable salt thereof. Specifically, a pre-step of separately coating inactive nuclei by adding pyridoxin hydrochloride in powder form, wherein the spray flow rate of the mixture containing one or more coating agents of 30-45% is specific. The spray flow rate of 40% (dewaxing) shellac in ethanol is 385-850 mg / min per 1 kg of inert nuclei, and the solid addition rate of the powder is 770 to 1700 mg / min per 1 Kg of inactive nuclei. Including the pre-step, wherein the relationship between the spray flow rate of the mixture containing the coating and the powdered mixture is 25:75-40:60.

In one embodiment, the methods of the invention further include simultaneous spraying of a mixture containing 30-45% by weight of one or more coatings, and a therapeutically effective amount of pyridoxin or a pharmaceutically acceptable salt thereof. In particular, a pre-step of separately coating inactive nuclei by adding pyridoxin hydrochloride in powder form, the spray flow rate of the mixture containing 30-45% one or more coatings is 1 Kg. 385 to 850 mg / min per inert nucleus of the powder, the solid addition rate of the powder was 770 to 1700 mg / min per 1 kg of inert nucleus, the spray flow rate of the mixture containing the coating and the solid addition of the powdered mixture. The relationship with rate is 25:75-40:60 and the coatings are microcrystalline cellulose, hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), shellac, polyethylene glycol (PEG) 6000, guar gum and starch. Includes a pre-step, which is selected from the group consisting of, specifically (dewaxing) starch.

In one embodiment, the methods of the invention further include simultaneous spraying of a mixture containing 30-45% by weight of one or more coatings, and a therapeutically effective amount of pyridoxin or a pharmaceutically acceptable salt thereof. , Specifically a pre-step of separately coating inactive nuclei by adding pyridoxin hydrochloride in power form, a mixture containing 30-45% by weight of one or more coatings. The spray flow rate is 385-850 mg / min per 1 kg of inert nuclei, the solid addition rate of the powder is 770-1700 mg / min per 1 kg of inactive nuclei, and the spray flow rate and powdering of the mixture containing the coating. The relationship between the solid addition rate of the mixture is 25:75-40:60, with a therapeutically effective amount of pyridoxin or a pharmaceutically acceptable salt thereof, specifically pyridoxin hydrochloride in powder form. It comprises a previous step in which the weight ratio to and from the mixture containing the coating is 25:75 to 40:60, specifically 1: 2.

In one embodiment, the methods of the invention further include simultaneous spraying of a mixture containing 30-45% by weight of one or more coatings, and a therapeutically effective amount of pyridoxin or a pharmaceutically acceptable salt thereof. , Specifically a pre-step of separately coating inactive nuclei by adding pyridoxin hydrochloride in powder form, the spray flow rate of the mixture containing 30-45% by weight of one or more coatings. Is 385-850 mg / min per 1 kg of inert nuclei, the solid addition rate of the powder is 770-1700 mg / min per 1 Kg of inactive nuclei, the spray flow rate of the mixture containing the coating and the powdered mixture. The relationship with the solid addition rate is 25:75-40:60, comprising the previous step, wherein the pyridoxin or a pharmaceutically acceptable salt thereof, in particular the pyridoxin hydrochloride, has a particle size of 100 μm or less. ..

In one embodiment, the methods of the invention are simultaneous spraying of a mixture containing 30-45% by weight of one or more coatings, and a therapeutically effective amount of pyridoxin or a pharmaceutically acceptable salt thereof. By adding, it further comprises a pre-step of separately coating the inert nuclei, the mixture containing one or more coatings containing one or more organic solvents specifically 65 per kg pellet. A solution further comprising an amount of ~ 83 g of solvent, more specifically 71 g of solvent per 1 kg of pellet, wherein the mixture has a total solvent concentration of 55-70 wt%, specifically 60 wt. This is a method having a% solvent. In one embodiment, the method is a method in which the mixture containing the dressing is a solution further comprising one or more organic solvents as defined above.

In one embodiment, the method of the invention further comprises 5 to 15 weights of pellets of doxylamine or a pharmaceutically acceptable salt thereof, specifically doxylamine succinate, having an active coating layer inside. Includes simultaneous spraying of a mixture containing one or more enteric coatings, and coating by adding 5.5-6.0 g of pore-forming agent per 1 kg of inert nucleus in powder form. In a further step, the spray rate of the mixture containing 5-15 wt% one or more enteric coatings is 445-1000 mg / min per 1 kg of inert nucleus and solid addition of the pore-forming agent. It comprises a further step where the rate is 45-100 mg / min per 1 kg of inert nucleus and the relationship between the spray flow rate of the mixture containing the coating and the solid addition rate is 87: 13-93: 7.

In one embodiment, the method of the invention further comprises 5-15% pellets of doxylamine or a pharmaceutically acceptable salt thereof, specifically doxylamine succinate, having an active coating layer inside. Further comprising co-spraying a mixture containing one or more enteric coatings of, and coating by adding 5.5-6.0 g of pore-forming agent per 1 kg of inert nucleus in powder form. In the process, the spray flow rate of the mixture containing 5 to 15% by weight of one or more enteric coatings is 445 to 1000 mg / min per 1 kg of inert nuclei, and the solid addition rate of the pore-forming agent. Is 45 to 100 mg / min per 1 kg of inert nuclei, the relationship between the spray flow rate of the mixture containing the coating and the solid addition rate is 87: 13 to 93: 7, and the enteric coating is described above. Including a further step, as defined in, specifically a methacrylic acid-methyl methacrylate copolymer (Eudragit L).

In one embodiment, the method of the invention further comprises pellets of doxylamine or a pharmaceutically acceptable salt thereof, specifically a pellet of doxylamine succinate, with an inner active release coating layer, 5-15. A further step comprising simultaneous spraying of the mixture with weight% enteric coating and coating by adding 5.5-6.0 g of pore-forming agent per 1 kg of inert nucleus in powder form. The spray flow rate of the mixture containing 5 to 15% of one or more enteric coatings is 445 to 1000 mg / min per 1 kg of inert nuclei, specifically 910 mg per 1 kg of inactive nuclei. / Min, the solid addition rate of the pore-forming agent is 45-100 mg / min per 1 kg of inert nucleus, and the relationship between the spray flow rate of the mixture containing the coating and the powdered mixture is 87:13. ~ 93: 7, specifically 90:10, comprising a further step, wherein the pore-forming agent is as defined above, specifically talc.

In one embodiment, the method of the invention further comprises pellets of doxylamine or a pharmaceutically acceptable salt thereof, in particular a pellet of doxylamine succinate, having an active release coating layer inside, 5-15. Simultaneous spraying of the mixture with weight% enteric coating and 5.5-6.0 g of pore-forming agent per 1 kg of inert nuclei, specifically 5.7 g per 1 kg of inactive nuclei. A further step comprising coating by adding the pore forming agent in powder form, wherein the mixture containing 5 to 15% by weight of the enteric coating agent specifically comprises 1 kg of one or more organic solvents. A mixture further comprising 48-55 g of solvent per inactive nucleus, more specifically 51 g of solvent per 1 kg of inert nucleus, wherein the mixture is 85-95 wt% total solvent. It comprises a further step having a concentration, more specifically 90% by weight of solvent. In one embodiment, the method is a method in which the mixture containing the dressing is a solution further comprising one or more organic solvents as defined above.

In one embodiment, the method of the invention comprising preparing a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof by the following steps:
Doxylamine with an inner active coating layer and an intermediate enteric coating layer or pellets of pharmaceutically acceptable salts thereof, 2.0-7.5 wt% enteric coating and 15.0-35. A step of co-spraying a mixture containing a 0.0% by weight modified release coating in a weight ratio of 5:95 to 30:70 and adding a pore-forming agent in powder form to cover the mixture, comprising the coating. The spray flow rate of the mixture is 300-1200 mg / min per 1 kg of inert nuclei, and the solid addition rate of the pore-forming agent is 75-500 mg / min per 1 kg of inactive nuclei, specifically 1 kg. The process is 85-425 mg / min per inert nucleus and the relationship between the spray flow rate of the mixture containing the coating and the rate of addition of the pore-forming agent in solid form is 90: 10-60: 40. ..

In one embodiment, the method of the invention comprising preparing a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof by the following steps:
5. Simultaneous spraying of pellets of doxylamine with an inner active release coating layer or a pharmaceutically acceptable salt thereof, with a mixture containing 5-15% enteric coating, and 1 kg of inert nuclei. A step of coating by adding 5 to 6.0 g of a pore-forming agent in powder form, inactive with a spray flow rate of 1 kg of a mixture containing 5 to 15% by weight of one or more enteric coatings. The solid addition rate of the pore-forming agent is 45-100 mg / min per 1 kg of inert nuclei, between the spray flow rate of the mixture containing the coating and the solid addition rate. The relationship in is 87:13 to 93: 7, step;
Pellets of doxylamine with an inner active coating layer and an intermediate enteric coating layer or a pharmaceutically acceptable salt thereof, 2.0-7.5 wt% enteric coating and 15.0-. A step of co-spraying a mixture containing 35.0% by weight of the modified release coating in a weight ratio of 5:95 to 30:70 and adding the pore-forming agent in powder form to coat the coating. The spray flow rate of the containing mixture is 300 to 1200 mg / min per 1 kg of inert nuclei, and the solid addition rate of the pore-forming agent is 75 to 500 mg / min per 1 kg of inactive nuclei, specifically 1 Kg. 85-425 mg / min per inert nucleus, and the relationship between the spray flow rate of the mixture containing the coating and the rate of addition of the pore-forming agent in solid form is 90: 10-60: 40. Process.

In one embodiment, the method of the invention comprising preparing a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof by the following steps:
Simultaneous spraying of a mixture containing 30-40% by weight of one or more coatings, and a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof and 22-30% by weight of a pore-forming agent. And, if necessary, the step of separately coating the inert nuclei by adding a powdered mixture with one or more pharmaceutically acceptable excipients, 30-40% by weight. The spray flow rate of the mixture containing one or more of the coatings is 445-1000 mg / min per 1 kg of inert nuclei and the solid addition rate of the powdered mixture is 1.64-3 per 1 Kg of inactive nuclei. .62 g / min, the relationship between the spray flow rate of the mixture containing the coating and the solid addition rate of the powdered mixture is 15:85-25:75, step;
Simultaneous spraying of pellets of doxylamine with an inner active coating layer or a pharmaceutically acceptable salt thereof with a mixture containing 5-15% enteric coating, and 5.5 per kg of inert nuclei. A step of coating by adding up to 6.0 g of a pore-forming agent in powder form, inactive with a spray flow rate of 1 kg of a mixture containing 5 to 15% by weight of one or more enteric coatings. 445-1000 mg / min per nucleus, solid addition rate of pore-forming agent 45-100 mg / min per 1 kg of inert nucleus, between spray flow rate and solid addition rate of the mixture containing the coating. The relationship is 87:13 to 93: 7, process;
Pellets of doxylamine with an inner active coating layer and an intermediate enteric coating layer or a pharmaceutically acceptable salt thereof, 2.0-7.5 wt% enteric coating and 15.0-. A step of co-spraying a mixture containing 35.0% by weight of the modified release coating in a weight ratio of 5:95 to 30:70 and adding the pore-forming agent in powder form to coat the coating. The spray flow rate of the containing mixture is 300 to 1200 mg / min per 1 kg of inert nuclei, and the solid addition rate of the pore-forming agent is 75 to 500 mg / min per 1 kg of inactive nuclei, specifically 1 Kg. 85-425 mg / min per inert nucleus, and the relationship between the spray flow rate of the mixture containing the coating and the rate of addition of the pore-forming agent in solid form is 90: 10-60: 40. Process.

In one embodiment, a method of the invention comprising preparing a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by the following steps:
Pellets of pyridoxin or a pharmaceutically acceptable salt thereof having an inner active coating layer, specifically pellets of doxylamine succinate, 2.0-7.5 wt% enteric coating and 15. It is a step of coating by simultaneously spraying and simultaneously spraying a mixture containing 0 to 35.0% by weight of a modified release coating agent at a weight ratio of 5:95 to 30:70, and adding a pore-forming agent in powder form. The spray flow rate of the mixture containing the coating agent is 300 to 1200 mg / min per 1 kg of inert nuclei, and the solid addition rate of the pore-forming agent is 75 to 500 mg / min per 1 kg of inactive nuclei. Specifically, it is 85 to 425 mg / min per 1 kg of inert nuclei, and the relationship between the spray flow rate of the mixture containing the coating agent and the addition rate of the pore forming agent is 90: 10 to 60:40. , Process.
In one embodiment, a method of the invention comprising preparing a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by the following steps:
Inactive nuclei by co-spraying a mixture containing 30-45% of one or more coatings and adding a therapeutically effective amount of pyridoxin or a pharmaceutically acceptable salt thereof in powder form. In a separate coating step, the spray flow rate of the mixture containing one or more coatings of 30-45% is 385-850 mg / min per 1 kg of inert nuclei and the solid addition rate of the powder is 1 Kg. 770 to 1700 mg / min per inert nucleus and the relationship between the spray flow rate of the mixture containing the coating and the powdered mixture is 25:75-40:60, step;
Pellets of pyridoxin or a pharmaceutically acceptable salt thereof with an inner active coating layer, specifically pellets of doxylamine succinate, 2.0-7.5 wt% enteric coating and 15 In the step of coating by co-spraying and co-spraying a mixture containing 0 to 35.0 wt% modified release coating at a weight ratio of 5:95 to 30:70 and adding the pore-forming agent in powder form. The spray flow rate of the mixture containing the coating agent is 300 to 1200 mg / min per 1 kg of inert nuclei, and the solid addition rate of the pore-forming agent is 75 to 500 mg / min per 1 kg of inactive nuclei. Specifically, it is 85 to 425 mg / min per 1 kg of inert nuclei, and the relationship between the spray flow rate of the mixture containing the coating agent and the addition rate of the pore forming agent is 90: 10 to 60:40. There is a process.

In one embodiment, each of the above coating steps is carried out at a temperature of 10 ° C to 30 ° C, specifically at a temperature of 15 ° C to 25 ° C, and more specifically at a temperature of 17 ° C to 22 ° C. Performed at temperature.

In one embodiment, each one of the above coating steps is carried out with an air flow of ^{0-20 m 3 / h per 1 kg of inert nucleus, specifically 0-4 m 3} / per 1 kg of inert nucleus. It is carried out with the air flow of h. Air flow is controlled using an anemometer-type air intake detection system installed in the duct between the fan and the coated pan, or using another equivalent system.

In one embodiment, the method of the invention further comprises one or more additional steps of separately drying each one of the plurality of pellets obtained in each one of the coating steps to remove solvent and humidity. , And if necessary, but if powder is found to agglomerate into granules, it comprises another post-step of sieving multiple pellets. In one embodiment, the drying step is carried out at a temperature of 20 ° C to 60 ° C, preferably at a temperature of 25 ° C to 45 ° C.

In certain embodiments, the intercoating drying step is performed at a temperature of 15 ° C. to 45 ° C. with ^{a coating pan rate of 0 to 10 rpm and with an air flow of more than 1 m 3 / h per 1 kg of inert nucleus.} It takes place over an hour.

In certain embodiments, the step of drying the outer coating of the pellet is at a temperature of 15 ° C. to 60 ° C. with ^{a coating pan rate of 0-10 rpm and with an air flow of more than 1 m 3 / h per 1 kg of inert nucleus.} The procedure is preferably carried out at a temperature of 25 ° C to 50 ° C, more specifically at a temperature of 40 ° C to 45 ° C, for 8 hours or more and 12 hours or less.

In one embodiment, the method of the invention further has a sieving size of 500 μm or more and 1500 μm or less, specifically 600 μm or more and 1320 μm or less, more specifically 710 μm or more and 1180 μm. Includes one or more additional steps of sieving multiple pellets until they have the following sieving size.

In one embodiment, the method is a method in which the modified release complex unit oral dosage form exhibits a lysing profile according to the following:

10% to 35% by weight of doxylamine content dissolves in 0.1 N HCl medium (pH = 1) at 1 hour;

The medium is then replaced with a pH = 4.5 medium (0.05 M acetate buffer) and at 4 hours the cumulative 45% to 70% by weight of the initial doxylamine content dissolves;

The medium is then replaced with a medium with pH = 6.8 (0.05 M phosphate buffer) and at 7 hours, at least a cumulative 80% of the initial doxylamine content is dissolved;

10% to 35% by weight of the pyridoxine content dissolves in 0.1 N HCl medium (pH = 1) at 1 hour;

The medium is then replaced with a pH = 4.5 medium (0.05 M acetate buffer) and at 4 hours the cumulative 40% to 65% by weight of the initial pyridoxine content dissolves;

The medium is then replaced with a medium with pH = 6.8 (0.05 M phosphate buffer) and at 7 hours, at least a cumulative 80% of the initial pyridoxine content is dissolved;

However, the dissolution profile is measured at 37 ° C. ± 0.5 ° C. and 100 rpm using a United States Pharmacopeia Type II device (basket) with the composition in 900 mL of the corresponding medium / buffer.

In one embodiment, the modified release complex unit oral dosage form comprises a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof and pyridoxine or a pharmaceutically acceptable salt thereof. Including a second plurality of modified release pellets
A first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof.
・ Inactive nucleus;
• A therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, 7-11% by weight of one or more dressings, and 20-28% by weight of one or more pore-forming agents. An inner active coating layer containing, if necessary, one or more pharmaceutically acceptable excipients;
An intermediate enteric release coating layer comprising 45-65% by weight of one or more enteric coating and 55-35% by weight of one or more pore-forming agents; and 8-14 by weight. % Of enteric coating, 38-46% by weight of one or more modified release coatings, and 42-52% by weight of one or more pore-forming agents on the outside. Includes modified release coating layer
And a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof.
・ Inactive nucleus;
An inner active dressing containing a therapeutically effective amount of pyridoxin or a pharmaceutically acceptable salt thereof and 14-20% by weight of one or more dressings; and-2-6% by weight. Outer modified release comprising one or more enteric coatings, 30-45% by weight of one or more modified release dressings, and 50-65% by weight of one or more pore-forming agents. The method of the invention comprising a coating layer.

In one embodiment, the method of the invention further comprises a first plurality of pellets of doxylamine or a pharmaceutically acceptable salt thereof and a second plurality of pellets of pyridoxine or a pharmaceutically acceptable salt thereof. Includes a further step of encapsulating, specifically in a hard capsule.

The encapsulation step can be performed by any method known in the art.

Throughout the description and claims, the word "comprise" (including) and variants of the word are not intended to exclude other technical features, additives, components or steps. Further, the word "comprise" includes the case of "consisting of" (consisting of). Further objects, advantages and features of the invention will be apparent to those of skill in the art when considering the description, or may be understood by the practice of the invention. The following examples are provided by way of example and are not intended to be a limitation of the present invention. In addition, the invention includes all possible combinations of the particular embodiments and preferred embodiments described herein.

1. 1. The method of the invention for producing capsules of pellets of doxylamine succinate and pyridoxine hydrochloride.

1.1. Quantitative Composition per Hard Capsule The amount of each component per capsule is as follows:

1.2 Quantitative composition per multiple pellets

1.2.1. Composition of Doxylamine Succinate Pellet The amount of each component per batch of about 180 kg of doxylamine succinate pellets is as follows:

1.2.2. Pyridoxine Hydrochloride Pellet Composition The amount of each component per batch of about 180 kg of pyridoxine hydrochloride pellets is as follows:

1.3. Preparation method by powder coating

1.3.1. Population of doxylamine succinate pellets A. Phase Preparation A powdered mixture for preparing an active coating layer inside Phase 1: Doxylamine succinate, aerosil200pharma, and talc disclosed above in the above amounts were mixed in a coated pan.

Binding solution for preparing the active coating layer inside Phase 2-The above amounts of Povidone K30 (20% ethanol solution) and (dewaxing) shellac (40% ethanol solution) were mixed.

Phase 3-Coating solution for preparing the outer coating: The above amounts of (dewaxed) shellac (40% ethanol solution) and Eudragit L (10% acetone solution) were mixed.

B. Preparation method-Inner active coating layer The granular sugar was transferred to a coating pan, and then phase 2 of the binding solution was sprayed at a spray flow rate of 100 g / min so as to cover the granular sugar kept in a rotating state in the coating pan. .. While Phase 2 was sprayed, Phase 1 of the powdered mixture was added (in solid form) over the granular sugar at a solid addition rate of 370 g / min. The spraying step was performed at a rotation speed of 16 rpm while maintaining the core temperature of the pellet between 17 ° C and 22 ° C ^{and the air flow below 100 m 3 / h.}

The coated pellet thus obtained is kept rotating in the coated pan at a speed configured between 0 and 10 rpm and ^{with an air flow of> 130 m 3} / h for more than 2 hours at room temperature. Drying over time gave dry coated pellets with an active coating layer on the inside containing the active ingredient. If necessary, the dried pellets could be screened and discarded powders and agglomerates of undesired particle size.

Intermediate intestinal release coating layer The coated active pellet obtained in the previous step was sprayed with a mixture of Eudragit L (10% acetone solution) at a spray flow rate of 100 g / min per 1 kg of inert nucleus. While the Eudragit is sprayed, the talc in solid form is added at a solid addition rate of 10 g / min and 16 rpm while maintaining the core temperature of the pellet between 17 ° C and 22 ° C ^{and the air flow below 100 m 3 / h.} In addition to covering the pellet at a rotational speed, pellets were obtained that were coated with an inner active coating layer and an intermediate intestinal release coating layer. The resulting coated pellets were dried at room temperature for more than 1 hour at a rate configured between 0 and 10 rpm and kept rotating in the coated pan with an air flow of> ^{130 m 3 / h.}

-Outer modified release coating layer Then, Phase 3 was sprayed at a spray flow rate of 100 g / min so as to cover the two-layer coating pellet obtained in the previous step. While the phase 3 is sprayed, the talc is rotated at a solid addition rate of 20 g / min and 16 rpm while maintaining the core temperature of the pellet between 17 ° C and 22 ° C ^{and the air flow below 100 m 3 / h.} Added in solid form at speed. The resulting coated pellets are kept rotating in the coated pan at a speed configured between 0 and 10 rpm and ^{with an air flow of> 130 m 3} / h at 40-45 ° C. for 8 hours or more and 12 It was dry for hours.

The pellet thus obtained has the desired dissolution profile. If necessary, the dried pellets could be screened and discarded powders and agglomerates of undesired particle size.

The modified release pellets of doxylamine succinate thus obtained were stored in a sealed high density polyethylene drum can in a 50 kg sealed double food and drug standard polyethylene bag.

1.3.2. Multiple pyridoxine hydrochloride pellets

A. Phase Preparation Phase 4-Coating solution for preparing the outer coating: The above amounts of (dewaxed) shellac (40% ethanol solution) and Eudragit L (10% acetone solution) were mixed.

B. Preparation method-Inner active coating layer The granular sugar is transferred to a coating pan, and then a (dewaxed) shellac solution (40% ethanol solution) is applied to the coating pan at a rotation speed of 16 rpm s and a spray flow rate of 100 g / min. Then, it was sprayed so as to cover the granular sugar kept in the rotating state. While the shellac solution (40% ethanol solution) is sprayed, pyridoxine hydrochloride is applied while maintaining the core temperature of the pellet between 17 ° C and 22 ° C and the air flow below ^{100 m 3 / h.} The mixture was added in solid form so as to cover the granular sugar at a solid addition rate of 200 g / min.

The coated pellet thus obtained is kept rotating in the coated pan at a speed configured between 0 and 10 rpm and ^{with an air flow of> 130 m 3} / h for more than 2 hours at room temperature. Drying over time gave dry coated pellets with an active coating layer on the inside containing the active ingredient. If necessary, the dried pellets could be screened and discarded powders and agglomerates of undesired particle size.

-Outer modified release coating layer Phase 4 was sprayed on the coated active pellets obtained in the previous step at a flow rate of 100 g / min. While the phase 4 is sprayed, the talc is added at a solid addition rate of 50 g / min and a rotation speed of 16 rpm while maintaining the core temperature of the pellet between 17 ° C and 22 ° C ^{and the air flow below 100 m 3 /.} Was added in solid form. The resulting coated pellets are kept rotating in the coated pan at a speed configured between 0 and 10 rpm and ^{with an air flow of> 130 m 3} / h at 40-45 ° C. for 8 hours or more and 12 It was dry for hours.

The pellet thus obtained has the desired dissolution profile. If necessary, the dried pellets could be screened and discarded powders and agglomerates of undesired particle size.

The modified release pellets of pyridoxine hydrochloride thus obtained were stored in a sealed high-density polyethylene drum can in a 50 kg sealed double food-pharmaceutical standard polyethylene bag.

Capsule filling Each hard capsule is filled with 60 mg of a modified release pellet of doxylamine succinate and 60 mg of a modified release pellet of pyridoxine hydrochloride as defined above, in a Bosch Zanussi E48 automatic capsule filling machine. Filled using.

2. 2. Dissolution test

Dissolved profile The desired lysed profile was achieved in the intestinal tract due to the slight dissolution of both doxylamine succinate and pyridoxine hydrochloride under gastric conditions, as well as a major therapeutic concentration due to its rapid dissolution rate. Need that. In particular, the preparation method of the present invention makes it possible to obtain capsules filled with such modified release pellets of doxylamine succinate and modified release pellets of pyridoxine hydrochloride and showing a lysing profile according to the following. Yes: Yes:

10% to 35% by weight of doxylamine content dissolves in 0.1 N HCl medium (pH = 1) at 1 hour;
The medium is then replaced with a pH = 4.5 medium (0.05 M acetate buffer) and at 4 hours the cumulative 45% to 70% by weight of the initial doxylamine content dissolves;
The medium is then replaced with a medium with pH = 6.8 (0.05 M phosphate buffer) and at 7 hours, at least a cumulative 80% of the initial doxylamine content is dissolved;
10% to 35% by weight of the pyridoxine content dissolves in 0.1 N HCl medium (pH = 1) at 1 hour;
The medium is then replaced with a pH = 4.5 medium (0.05 M acetate buffer) and at 4 hours the cumulative 40% to 65% by weight of the initial content of pyridoxin dissolves; and then the medium is pHed. = Replaced with 6.8 medium (0.05 M phosphate buffer), at 7 hours, at least a cumulative 80% of the initial content of pyridoxin is dissolved.

However, the dissolution profile is measured at 37 ° C. ± 0.5 ° C. and 100 rpm using a United States Pharmacopeia Type II device (basket) with the composition in 900 mL of the corresponding medium / buffer.

Dissolution bath conditions ・ Paddle speed: 100 rpm
-Temperature of dissolution medium: 37 ° C ± 0.5 ° C
-Dissolution medium: Hydrochloric acid, 0.1N
・ Container volume: 900 mL
・ Time: 1 hour ・ Dissolution medium: pH4.5; 0.05M acetate buffer ・ Container volume: 900mL
・ Time: 1st to 4th hours ・ Dissolution medium: pH 6.8; 0.05M phosphate buffer ・ Container volume: 900mL
-Time: 4th to 7th hours Chromatographic analysis conditions-Sample preparation: Take an amount of about 10 ml, filter with a 0.70 μm membrane filter, and then filter with another 0.22 μm membrane filter.
-Flux: 1 mL / min-Column: Kromasil 100-5 C18, 150 x 4.0 mm
-Phase: Methanol / water-Injection amount: 100 μL
-Excitation wavelength: 220 nm
-Chromatography time: 25 minutes-Aqueous phase: Ammonium acetate buffer (0.06M, pH 5.0) + 0.1% sodium hexanesulfonate (PICB6)) :.
・ Gradient:

Results Dissolved profile of capsules of the invention containing pellets of doxylamine succinate and pyridoxine hydrochloride

Dissolving profiles as disclosed above indicate that the capsules of the invention have the required lytic profile. Thus, dissolution of both doxylamine succinate and pyridoxine hydrochloride when exposed to gastric conditions is at least 10% of the total amount in 1 hour, and after 4 hours at least 40% of doxylamine succinate and pyridoxine hydrochloride It dissolves when exposed to duodenal conditions (pH = 4.5) and after 7 hours at least 80% of doxylamine succinate and pyridoxine hydrochloride dissolve when exposed to colonic conditions.

Reference list 1. International Publication WO2013 / 123569 Publication No. 2. International Publication WO2016 / 029290 Gazette

Claims (15)

A first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof and a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof.
The first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof
・ Inactive nucleus;
• A therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more dressings, one or more pore-forming agents, and one or more pharmaceuticals if necessary. An inner active coating layer containing an acceptable excipient;
An intermediate enteric release dressing containing one or more enteric coatings and one or more pore-forming agents; and-one or more enteric coatings and one or more Includes an outer modified release coating layer containing a modified release coating and one or more pore forming agents.
The second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof
・ Inactive nucleus;
An inner active dressing containing a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof; and one or more enteric coatings and one. A method for preparing a modified release complex unit oral dosage form comprising an outer modified release coating layer comprising one or more modified release dressings and one or more pore-forming agents. ,
The following process:
2.0 to 7.5% by weight of the enteric coating and 15 the pellets of doxylamine or a pharmaceutically acceptable salt thereof having the inner active coating layer and the intermediate enteric coating layer. By co-spraying a mixture containing 0 to 35.0% by weight of the modified release coating in a weight ratio of 5:95 to 30:70 and coating by adding the pore forming agent in powder form. The step of preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the spray flow rate of the mixture containing the coating is 300-1200 mg per 1 kg inactive nucleus. / Min, the solid addition rate of the pore-forming agent is 75-500 mg / min per 1 kg of inert nuclei, the spray flow rate of the mixture containing the coating and the pore-forming agent in solid form. The relationship between the addition rate and the step is 90: 10-60: 40, and the pellet of pyridoxin having the active coating layer on the inside or a pharmaceutically acceptable salt thereof, from 2.0 to 2.0. A mixture containing 7.5% by weight of the enteric coating and 15.0 to 35.0% by weight of the modified release coating in a weight ratio of 5:95 to 30:70 was co-sprayed to form the pores. A step of preparing the second plurality of modified release pellets of pyridoxin or a pharmaceutically acceptable salt thereof by coating by adding the agent in powder form, wherein the mixture containing the coating agent. The mixture containing the coating agent, the spray flow rate is 300 to 1200 mg / min per 1 kg of inert nuclei, the solid addition rate of the pore-forming agent is 75 to 500 mg / min per 1 kg of inactive nuclei. A method comprising the steps, wherein the relationship between the spray flow rate of the mixture and the rate of addition of the pore-forming agent in solid form is 90: 10-60: 40. A step of preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof as defined in claim 1, wherein the solid addition rate of the pore-forming agent is 1 kg. 88-195 mg / min per inert nucleus of the step;
And, in the step of preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof as defined in claim 1, the solid addition rate of the pore-forming agent is increased. 193 to 425 mg / min per 1 kg of inert nucleus, step:
The method according to claim 1. The step of preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof as defined in claim 1, wherein the spray flow rate of the mixture containing the coating agent and the like. The relationship between the solid addition rate of the pore-forming agent and the solid addition rate is 90: 10 to 60:40.
And • A step of preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof as defined in claim 1, wherein the spray flow rate of the mixture containing the coating agent. The relationship between and the solid addition rate of the pore-forming agent is 90: 10-60: 40, step;
The method according to claim 1 or 2, wherein the method comprises. The method according to any one of claims 1 to 3, wherein the mixture comprises 2.5 to 5.5% by weight of the enteric coating and 18 to 30% by weight of the modified release coating. Pre-process to coat separately:
By co-spraying the mixture containing 5-15% of the enteric coating and adding 5.5-6.0 g of the pore-forming agent per 1 kg of inert nuclei in powder form, said inner. The step of coating the pellet of doxylamine with an active coating layer or a pharmaceutically acceptable salt thereof, wherein the spray flow rate of the mixture containing 5 to 15% by weight of one or more enteric coatings is The solid addition rate of the pore-forming agent is 45-100 mg / min per 1 kg of inactive nuclei, and the spray flow rate of the mixture containing the coating agent is 45-100 mg / min per 1 kg of inactive nuclei. The relationship between and the solid addition rate is 87:13 to 93: 7, step;
And • The inert by simultaneous spraying of a mixture containing 30-45% of one or more coatings and the addition of the therapeutically effective amount of pyridoxin or a pharmaceutically acceptable salt thereof in powder form. In the step of coating a solid core, the spray flow rate of the mixture containing one or more coating agents of 30 to 45% is 385-850 mg / min per 1 kg of inert core, and the solid addition of the powder. A step;
The method according to any one of claims 1 to 4, further comprising. The process according to any one of claims 1 to 5, wherein the particle size of doxylamine or a pharmaceutically acceptable salt thereof and pyridoxine or a pharmaceutically acceptable salt thereof is 1 μm to 250 μm. Simultaneous spraying of a mixture containing 30-40% by weight of one or more coatings, and a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof and 22-30% by weight of the pore-forming agent. And, if necessary, the step of coating the inert nucleus by adding a powdered mixture with one or more pharmaceutically acceptable excipients, wherein 30-40% by weight. The spray flow rate of the mixture containing one or more coatings is 445-1000 mg / min per 1 kg of inert nuclei and the solid addition rate of the powdered mixture is 1.64 to 1.64 per 1 Kg of inert nuclei. An additional step comprising a step of 3.62 g / min, wherein the relationship between the spray flow rate of the mixture containing the coating and the solid addition rate of the powdered mixture is 15:85-25:75;
The method according to any one of claims 1 to 6, further comprising. The method according to any one of claims 1 to 7, wherein the pore-forming agent has a particle size of 1 μm to 250 μm. The method according to any one of claims 1 to 8, wherein the modified release type composite unit oral dosage form comprises doxylamine succinate and pyridoxine hydrochloride. One of claims 1 to 9, wherein the modified release type composite unit oral dosage form is a hard capsule containing 5 mg to 50 mg of doxylamine succinate per capsule and 5 mg to 50 mg of pyridoxine hydrochloride per capsule. The method described in. The coating on the inner active coating layer of pellets of doxylamine or a pharmaceutically acceptable salt thereof is selected from the group consisting of polyvinylpyrrolidone, shelac, hypromellose, hydroxypropyl cellulose, microcrystalline cellulose and mixtures thereof. , Or, in the alternative, the method of any one of claims 1-10, wherein the pore-forming agent is selected from the group consisting of talc, micropulverized sugar, sodium chloride or potassium chloride, and mixtures thereof. The enteric coating agent is a copolymer of methacrylic acid and methyl methacrylate, a copolymer of methacrylic acid and methyl acrylate, cellulose acetate, hydroxypropylmethyl phthalate, polyvinyl acetatortophthalate, sodium alginate, cellulose acetate, trimellithate. The method according to any one of claims 1 to 11, which is selected from the group consisting of a mixture thereof. Further comprising the further step of separately drying each one of the plurality of pellets obtained in each one of the coating steps, for which the drying step is such that each of the solvents used in the process is less than 5000 ppm. The method of any one of claims 1-12, wherein the method is carried out at a temperature of 15 ° C. to 60 ° C. and ^{an air flow of more than 1 m 3 / (h / kg inert nucleus) over an appropriate period of time.} The modified release type composite unit oral dosage form
10% to 35% by weight of doxylamine content dissolves in 0.1 N HCl medium (pH = 1) at 1 hour;
The medium is then replaced with a pH = 4.5 medium (0.05 M acetate buffer) and at 4 hours the cumulative 45% to 70% by weight of the initial doxylamine content dissolves;
The medium is then replaced with a pH = 6.8 medium (0.05 M phosphate buffer) and at 7 hours, at least a cumulative 80% of the initial doxylamine content is dissolved;
10% to 35% by weight of the pyridoxine content dissolves in 0.1 N HCl medium (pH = 1) at 1 hour;
The medium is then replaced with a pH = 4.5 medium (0.05 M acetate buffer) and at 4 hours the cumulative 40% to 65% by weight of the initial pyridoxine content dissolves;
The medium was then replaced with a pH = 6.8 medium (0.05 M phosphate buffer) and at 7 hours showed a dissolution profile according to the dissolution of at least a cumulative 80% of the initial pyridoxine content.
The dissolution profile is measured at 37 ° C. ± 0.5 ° C. and 100 rpm using a United States Pharmacopeia Type II device (basket) and placing the composition in 900 mL of the corresponding medium / buffer.
The method according to any one of claims 1 to 13. The modified release complex unit oral dosage form comprises a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof and a second plurality of pyridoxine or a pharmaceutically acceptable salt thereof. Including modified release pellets
The first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof
・ Inactive nucleus;
• A therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, 7-11% by weight of one or more dressings, and 20-28% by weight of one or more pore-forming agents. An inner active coating layer containing, if necessary, one or more pharmaceutically acceptable excipients;
An intermediate enteric release coating layer comprising 45-65% by weight of one or more enteric coating and 55-35% by weight of one or more pore-forming agents; and 8-14 by weight. % Of enteric coating, 38-46% by weight of one or more modified release coatings, and 42-52% by weight of one or more pore-forming agents on the outside. Includes modified release coating layer
The second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof
・ Inactive nucleus;
An inner active dressing containing a therapeutically effective amount of pyridoxin or a pharmaceutically acceptable salt thereof and 14-20% by weight of one or more dressings; and-2-6% by weight. Outer modified release comprising one or more enteric coatings, 30-45% by weight of one or more modified release dressings, and 50-65% by weight of one or more pore-forming agents. Including the coating layer,
The method according to any one of claims 1 to 14.